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Combined Modality Targeted Therapy of Pancreatic Cancer with Death Receptor

Combined Modality Targeted Therapy of Pancreatic Cancer with Death Receptor
死亡受体联合靶向治疗胰腺癌
批准号:
7962128
负责人:
DONALD J. BUCHSBAUM
金额:
$18.36万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-03-01 至 2015-02-28
关键词:
AccountingAdaptor Signaling ProteinAddressAdvanced Malignant NeoplasmAdverse effectsAgonistAmerican Society of Clinical OncologyAnimal ModelAntibodiesApoptosisApoptosis InhibitorAttentionBiological MarkersBiologyCancer CenterCancer ModelCancer PatientCancer cell lineCaspaseCell DeathCell LineCell surfaceCessation of lifeClinicalClinical TrialsCombined Modality TherapyComplexCredentialingDataDeath DomainDevelopmentDiseaseDisseminated Malignant NeoplasmDoctor of MedicineDoseEnrollmentEpidermal Growth Factor ReceptorEvaluationExhibitsExternal Beam Radiation TherapyFamilyFundingFutureGoalsGrantHepatocyteHumanHuman GenomeIn VitroInduction of ApoptosisInstructionLeadLicensingLigandsLiteratureMalignant NeoplasmsMalignant neoplasm of pancreasManuscriptsMediatingMembraneMinnesotaModalityModelingMolecularMolecular ProfilingMonoclonal AntibodiesMonoclonal Antibody C225Monoclonal Antibody TherapyMusNewly DiagnosedNormal CellPancreasPathway interactionsPatientsPharmaceutical PreparationsPhasePhase I Clinical TrialsPhase II Clinical TrialsPlayPredispositionPrimatesProductionProgress ReportsPropertyProteomicsProtocols documentationPublic HealthQuality ControlRNA HelicaseRadiationRadiation therapyRadiation-Sensitizing AgentsReagentRecruitment ActivityRegimenRegulationReportingReproduction sporesResearchResistanceRoleScienceSignal TransductionSiteStagingTNFRSF10A geneTNFSF10 geneTailTechnologyTestingTherapeuticTherapeutic AgentsTissue SampleTissuesToxic effectToxicologyTranslatingTranslational ResearchTranslationsTreatment EfficacyTreatment ProtocolsTumor Cell LineUniversitiesUniversity of Alabama at Birmingham Cancer CenterUniversity of Minnesota Cancer CenterXenograft ModelXenograft procedureabstractingassay developmentbasecancer cellcancer therapychemotherapeutic agentchemotherapyclinical efficacycytotoxicitydocetaxeldrug developmentgemcitabinein vivoindustry partnerinhibitor/antagonistirinotecanmalignant breast neoplasmneoplastic cellnovelnovel therapeuticsoxaliplatinpancreas xenograftpancreatic neoplasmpatient populationpre-clinicalpreclinical studyprogramsprotein complexreceptorresponsesmall moleculesynergismtherapeutic targettreatment strategytrendtumortumor immunology

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中文摘要
翻译
项目总结(见说明); 该提案是原SPORE赠款中项目2的延续。关于这项建议,我们有 通过体外研究、动物实验和动物实验,开发了一种抗DRS单克隆抗体治疗胰腺癌的方法, 模型疗效,并与行业合作伙伴(第一三共),I期和最近完成的II期试验 在胰腺癌中。我们还发现了一种新的分子(DDX 3),它似乎在 调节抗DRS介导的细胞凋亡。在本建议书中,我们会探讨两项策略, 抗DRS单克隆治疗的功效,特别是在胰腺肿瘤细胞系中, 两种策略是评估单克隆抗DR 4试剂的添加或 加入凋亡级联的小分子调节剂。两种凋亡调节剂 评估的是AT-101(Bcl-2家族抑制剂)和AT-406(IAP家族抑制剂)。这两个战略将 使用体外分析和原位和转移性异种胰腺癌模型进行研究 最佳策略的第一阶段试验此外,我们将继续研究DDX 3和 DRS/DDX 3复合物作为肿瘤细胞对死亡受体介导的敏感性/抗性的推定生物标志物 抗肿瘤功效和作为抗DR介导的抗肿瘤作用的增强策略的靶标。
英文摘要
PROJECT SUMMARY (See instructions); This proposal is a continuation of Project 2 in the original SPORE grant. Pertinent to this proposal, we have developed an anti-DRS monoclonal antibody therapy for pancreatic cancer through in vitro studies, animal model efficacy and with an industry partner (Daiichi Sankyo), Phase I and recently completed Phase II trials in pancreatic cancer. We have also discovered a novel molecule (DDX3) which appears to play a major role in regulation of anti-DRS mediated apoptosis. In this proposal, we will explore two strategies to enhance the efficacy of anti-DRS monoclonal therapy especially in pancreatic tumor cell lines which are intermediate or resistant to anti-DRS. The two strategies are to evaluate the addition of a monoclonal anti-DR4 reagent or the addition of small molecule modulators ofthe apoptosis cascade. The two apoptosis modulators to be evaluated are AT-101, a Bcl-2 family inhibitor, and AT-406, an lAP family inhibitor. These two strategies will be studied using in vitro analysis and orthotopic and metastatic xenogeneic pancreatic cancer models leading to a Phase I trial of the best strategy. In addition, we will continue studies of DDX3 and the DRS/DDX3 complex as a putative biomarker for tumor cell sensitivity/resistance to death receptor mediated anti-tumor efficacy and as the target of enhancement strategies for anti-DR mediated anti-tumor effects.
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Therapy of pancreatic cancer with 212Pb-labeled B7-H3 specific Ab and LDE225
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